The
number of type 2 diabetes (T2D) patients has augmented sharply over the past
decades and become a major public health threat worldwide. Compelling evidence
demonstrates a transition from traditional (principally nutritionally dense)
diet to more energy-dense (Western-pattern) diet plays a pivotal role in
promoting the epidemic of T2D. With revolutionary advances in genotyping and
sequencing methodology, large-scale genome-wide association studies (GWASs)
have made great strides in unraveling the genetic basis of T2D, and
facilitating efforts to investigate gene-diet interaction. A great group of
studies have been performed to assess interactions between genetic factors and
dietary factors, mostly focusing on candidate genes and being conducted in
small-sized observational settings. Recently, reports from large scale
prospective cohorts and randomized clinical trials are emerging. In addition,
it remains a major challenge to convert the findings into public health and
medical practice.

As one of the leading causes of morbidity and mortality, diabetes has
become one of the leading health threats worldwide. Globally, the number of
diabetes patients has been predicated to be 552 million by 2030 [1]. Moreover,
more than 90% patients are classified as type 2 diabetes (T2D), and insulin
resistance and beta cell dysfunction are the major pathophysiologic basis of
T2D.

T2D is one of the major metabolic disorders closely related to environment
factors, such as lifestyle and diet. A large body of data from epidemiological
studies has consistently shown that several dietary factors are linked to risk
of T2D. For example, high intakes of trans- and saturated fat, refined grains,
red meats or processed meats, fried-foods and sugar-sweetened beverages have
been related to increased risk of T2D [2-5], whereas high consumption of whole
grains, fruits and vegetables, legumes, nuts, coffee, and moderate alcohol
reduced the T2D risk [2,4,6,7]. Particular dietary patterns stated by
combinations of different foods and nutrients have also been associated with
T2D risk [4,8].

Since 2007, application of genome-wide association studies (GWAS) in
population studies has made great breakthrough in uncovering the genetic basis
of T2D. HHEX and SLC30A8 were the first GWAS-identified new diabetes loci [9].

After then, larger-scale meta-analyses of GWAS have identified more
T2D-associated loci. The first round of meta-analysis by the Diabetes Genetics
Replication and Meta-analysis (DIAGRAM) consortium identified 6 novel loci [10],
and the second round meta-analysis [11] identified 12 additional loci. Another
including 21 cohort data of European decent GWAS meta-analysis conducted by the
Glucose and Insulin-Related Traits Consortium (MAGIC) identified 5 T2D
associated loci [12]. To date, around 70 loci have been confirmed as T2D
susceptibility loci [13,14].

It has been noted for a long time that response to environmental risk
factors and clinical interventions varies considerably between individuals,
suggesting that environmental factors, genetic components and their
interactions determine an individual’s risk for T2D [15,16]. To date,
interactions between genetic and environmental factors such as dietary factors
are hypothesized to raise T2D risk in a synergistic manner in most cases.
Defining the nature of gene-diet interactions that can be translated into the
public health setting may help optimize targeting of health interventions. In
this article, we focused on describing the latest rationale and evidence
concerning the interaction effect of gene and dietary factors on T2D. In
addition, we provide an interpretation of current findings and strategies and
offer a view for their future translation.

Why Do We Think Gene-Diet
Interaction Is Important to Type 2 Diabetes ?

The effects of individual genetic variants are generally modest. The
odds ratios (ORs) of each risk allele with target disease usually range from
1.1 to 1.3 [17]. Additionally, when all the identified genetic variants are
considered together, they only account for a small proportion of the disease
risk, meaning huge ‘missing heritability’ [18]. It is believed that
interactions between the genetic variants and environmental risk factors could
explain at least part of the missing heritability [19]. However, most of the
previous genetic researches did not consider the potential modification from
environmental factors.

A popular yet contentious explanation for why indigenous groups (whose
evolution has involved long periods of migrant, hunter-gatherer lifestyles, and
frequent famine) are so susceptible to the adverse consequences of
industrialized environments is termed as the “thrifty gene hypothesis” first
proposed by Neel in 1992 [20], which can explain the rapid increase of diabetes
and obesity in modern society. According to this hypothesis, the diabetes or
obesity-predisposing genotypes would have been advantageous in the early
evolutionary history because these genotypes promote fat deposition in
adipocytes, which protect human beings to survive at the period of famine
(positive selection). However, such genotypes become disadvantageous in modern
society when excessive automation and almost effortless access to energy-dense
foods, calorie accumulation and storage and over-nutrition has become popular
[20]. If the hypothesis is true, it may provide a judicious model to account
for the gene-diet interaction. However, evidence directly supporting the
hypothesis is largely lacking. Recently, Ayub et al. [21] tried to test the
hypothesis at 65 loci associated with T2D in samples of African, European, and
East Asian ancestry. The results failed to demonstrate that positive selection
has a powerful effect on driving the prevalence of T2D risk.

Even though, studies attempting to test the gene-environment
interaction have provided preliminary evidence to support that such
interactions between the genetic variants and environmental factors may exist.
The gene-diet interactions for diabetes-related traits have been reported since
mid-1990s [22]; nevertheless, the majority of these studies were performed in
relatively small cohorts, case-control studies, and less clinical trials. With
reliable interactions are discovered, the interaction information would be used
to improve predictive accuracy, and the precision medicine informed by
biomarker data would improve treatment outcomes. In addition, it will also be meaningful
for the implications to public health, medical practice and biology.

Gene-Diet
Interaction in Observational Studies

Most of the previous gene-diet interactions studies were performed in
observational investigations such as case-control and cohort studies, and a
small portion of those were conducted in clinical trial settings. Early studies
were often concentrated on the selected genetic variants in candidate genes,
while recent studies focused more on the GWAS-identified variants.

TCF7L2 is the strongest susceptibility gene
associated with T2D by far. Quite a few studies testing interactions between TCF7L2 variants and dietary factors,
such as whole grains, fat, protein, carbohydrate, and Mediterranean diet
(MedDiet) were emerging [23-26]. In the European Prospective Investigation into
Cancer and Nutrition (EPIC)-Potsdam cohort, the TCF7L2 rs7903146 genotypes were found to modify the inverse
association between whole-grain intake and diabetes risk (P for interaction =
0.016). In the carriers of C allele, whole-grain intake was significantly in
relation to a decreased diabetes risk (hazard ratio [HR] for 50 g portion/day =
0.86; 95% confidence interval [CI]: 0.75, 0.99); whereas the T-allele
attenuated the associations to null (HR=1.08; 95 % CI: 0.96, 1.23) [24]. The
investigators found that the TCF7L2
rs7903146 variant also modulated associations between fiber intakes and T2D in
a case-control study derived from the Malmö Diet and Cancer Study (MDCS) [26],
which included 5,216 non-diabetic controls and 1,649 diabetes cases. The
association between genetic effects with T2D risk increased with higher intake
of dietary fiber, with ORs ranging from 1.24 to 1.56 from the lowest to highest
quintile of fiber intake (P for interaction = 0.049). The MedDiet is deemed to
be an healthy dietary pattern, which includes proportionally high consumption
of olive oil, legumes, unrefined cereals, fruits, and vegetables, moderate to
high consumption of fish, moderate consumption of dairy products (mostly as
cheese and yogurt), moderate wine consumption, and low consumption of meat and
meat products. In a prospective study including 7,018 individuals with a median
follow-up of 4.8 years, it was found that adherence to the MedDiet could reduce
the increase in fasting plasma glucose and serum lipids levels related to TCF7L2 rs7903146 [26].

Another widely validated and well accepted T2D-related genetic locus is
zinc transporter-8 gene (SLC30A8).
The gene encodes ZnT-8, which transports zinc from the cytoplasm into insulin
secretary vesicles in pancreatic beta cells playing an important role in
insulin synthesis and secretion. Zinc is an essential trace element found in
most foods and facilitates catalytic, structural, and transcriptional actions
[27]. Plasma zinc concentrations have been reported to be associated with impaired
glucose regulation (IGR) and T2D risk in epidemiology studies.
Recently, one study was conducted by the Cohorts for Heart and Aging Research
in Genetic Epidemiology (CHARGE) consortium [28], including14-cohort
meta-analysis to assesses the interaction of 20 genetic variants related to
glycemic traits and zinc metabolism with dietary zinc intake (food sources),
and 5-cohort meta-analysis to assess the interaction with total zinc intake
(food sources and supplements) on fasting glucose levels among individuals of
European ancestry without diabetes. The data suggested that higher total zinc
intake might attenuate the glucose-raising effect of the A-allele of SLC30A8 rs11558471. Besides the
tentative evidence of interactions for variants in SLC30A8 and total zinc intake on fasting plasma glucose
concentrations, it was also found that higher whole-grain intake was associated
with less reduction in fasting insulin in those with the insulin-raising allele
of rs780094 (GCKR) (P for interaction
= 0.006) [29]. However, no interaction between the selected genetic variants
and dietary magnesium or dietary patterns was found.

In a study from China, the researchers reported a significant the
interaction of SLC30A8 rs13266634
with plasma zinc levels associated with T2D (P for interaction = 0.01) [30].
Each 10-µg/dl higher plasma zinc level was associated with a decreased risk of
T2D with multivariate-adjusted OR of 0.87 (95% CI 0.85-0.90). The associations
was more prominent in the TT homozygotes, each 10-µg/dl increment of plasma
zinc was associated with 22% (OR, 0.78; 95% CI, 0.72-0.85) lower odds of T2D;
while 17% (0.83; 0.80-0.87) and 7% (0.93; 0.90-0.97) lower odds were observed
in the CT and CC genotypes, respectively. Summarily, the C allele of rs13266634
was associated with higher odds of T2D and higher plasma zinc was related to
lower odds. SLC30A8 rs13266634
modulated the inverse association of plasma zinc concentrations with T2D.

In addition, in another large prospective cohorts study from southern
Sweden, significant interactions between the IRS1 and GIPR variants
with dietary fat and carbohydrate intakes on risk of incident T2D were recently
reported [32,33]. A protective association between the IRS1 rs2943641 T allele and T2D was restricted to women with low
carbohydrate intake (P for interaction = 0.01) and to men with low fat intake
(P for interaction = 0.02) [31]. Prospective cohort results showed that
AA-genotype carriers of GIPR rs10423928
consuming high-fat low carbohydrate diets had reduced T2D risk, whereas
high-carbohydrate low-fat diets benefitted the two thirds of population
homozygous for the T-allele [32].

Of note, several potential conceptual or methodological limitations
need to be acknowledged, since the majority of available gene-diet interaction
studies have focused on single nutrient or food. Firstly, in a real world, the
“single nutrient/food” approach may not adequately account for complicated
nutrient interactions in free-living populations. The cumulative effects of
combined nutrients/foods intake, such as dietary patterns or quality indexes,
may be more appropriate to be used in estimating gene-diet interactions.
Secondly, to use combined genetic effect in the gene-diet interaction tests is
a reasonable and effective way, especially when the individual genetic variation
effect is minor. A genetic risk score summing risk alleles for the established
susceptibility loci from GWAS has been widely used to represent the overall
genetic predisposition [33]. Even though less informatively at the biological
level, the genetic risk score is a powerful method for demonstrating an
interaction. In a previous and important study by Qi et al. [8], the authors
calculated a genetic risk score using a simple count method under an additive
genetic model, assuming that each single nucleotide polymorphisms (SNP) is
independently associated with T2D risk. It was found that the Western dietary
pattern was significantly associated with an increment risk of T2D only among
those with a high genetic risk score (≥ 12) than in those with a low genetic
risk score. Secondary analysis suggested the interaction was largely
attributable to the red and processed meat component of the Western diet. They
concluded that genetic predisposition might synergistically interact with a
Western dietary pattern in determining diabetes risk in men.

In a cross-sectional study by Yokoyama K et al [35], investigators
found that 1, 25-dihyroxyvitamin D (1, 25OHD) levels may be associated with
better chronic kidney disease (CKD) stages in patients with T2D and this
association was modified by vitamin D receptor (VDR) polymorphisms. The
positive association between 1, 25OHD and CKD stage was steeper in FokICT and
CC polymorphisms than FokITT polymorphisms.

Gene-Diet
Interaction in Clinical Trials

Randomized intervention trials may act as an alternative approach for
testing gene-diet interaction in prospective manner [36]. Randomization
minimizes the potential confounding effects or reverse causation that often
occurs in observational studies, which may gravely bias gene-diet interactions.
Specifically, in a randomized diet intervention trial, interventions are
prescribed and dietary factors are usually precisely defined. In addition, the
results may provide more direct evidence to instruct genetic-targeted diet
modifications in future public health and clinical practice, which is a unique
strength to gene-diet interaction in randomized intervention trials [23].
However, a major challenge of most of the existing clinical trials is their
power for detection of moderate gene-diet interactions due to relative small
size.

The Diabetes Prevention Program (DPP) is so far the largest randomized
controlled trial of lifestyle intervention and metformin for diabetes
prevention. gene-lifestyle interactions on incident T2D risk have been widely
tested in this trial, and significant interactions between lifestyle
intervention and genetic variants at TCF7L2
[36], WFS1 [37], other
established T2D-related loci [38, 39], established glucose- and
insulin-associated loci [39], common and rare variants at the MC4R [40] and SLC80A8 loci [41], as well as other candidate loci [42-44] have
been reported. For example, a stronger association between the TT homozygote of
TCF7L2 rs12255372 and the diabetes
risk was found in the placebo group (HR=1.81; 95%CI 1.19-2.75) than in the
lifestyle intervention groups, which was characterized as increased intake of
fiber, moderate exercise for at least 30 minutes per day and reduced intakes of
total fat and saturated fat. Although test of interaction was not statistically
significant (P for interaction > 0.10), these data suggested that healthy
diet intervention may attenuate the genetic effects on T2D risk.

Tübingen Lifestyle Intervention Program (TULIP) is another randomized
control clinical trial consisting of exercise and diet intervention with
decreased intake of fat and increased intake of fibers (participants were
instructed to eat at least 15 g fiber per 1,000 kcal), which found that the CC
genotype of TCF7L2 rs7903146 is
significantly related to greater weight loss in participants with high fiber
intake, but not in those with low fiber intake [45].

The Preventing Overweight Using Novel Dietary Strategies (Pounds
Lost) is a randomized clinical trial to assess the possible
advantage for reduced-calorie weight-loss diets that emphasizes different
macronutrient contents varying in carbohydrates, fat and protein in 811
participants for 2 years [46]. In the Pounds Lost trial [47], the T2D-related TCF7L2 rs12255372 significantly modified
the effect of fat intake on changes in Body Mass Index, total fat mass, and
trunk fat mass (all P < 0.05) at 6 months. Individuals with the TCF7L2 rs12255372 risk genotype may
reduce body adiposity by consuming a lower-fat diet. The FTO SNP rs1558902 was also reported to modulate dietary protein on
2-year changes in fat-free mass, total percentage of fat mass, and total-,
visceral-, and superficial adipose tissue mass [48]. A high-protein diet may be
beneficial for weight loss and improvement of body composition and fat
distribution in individuals with the risk allele of the FTO variant rs1558902.

Several other T2D-associated genetic variants have also been found to
modify diet interventions on weight change and improvement of insulin resistance
in the Pounds Lost trial [49,50], such as IRS1
SNP rs294364 and the amino acid metabolites related genotype PPM1K rs1440581. At 6 months,
participants with the IRS1 SNP
rs294364 risk-conferring CC genotype had greater decrease in weight loss than
those without this genotype in the highest-carbohydrate diet group; whereas the
genetic effect was not significant in subjects assigned to the
lowest-carbohydrate diet group (P for interaction = 0.03). Branched amino acids
(BCAAs) or aromatic amino acids (AAAs) were recently reported to be associated
with obesity, insulin resistance and T2D risk [51-53] and weight loss induced
by dietary intervention [54,55]. The firstly identified SNP from amino acid
metabolites GWAS was PPM1K rs1440581,
which was found to modify effect of dietary fat on weight loss and changes in
insulin resistance [50]. In the energy restricted high-fat diet group, at 6
months of intervention, the C allele of rs1440581was associated with less
weight loss (adjusted means: TT, -6.7kg; CT, -5.8kg; CC, -4.1 kg, respectively,
P for interaction = 0.001 in an
additive model), whereas no significant genetic effect was observed in the
low-fat diet group. The carriers of C allele had smaller decreases in serum
insulin and insulin resistance than those without this allele in high-fat diet
group, whereas an opposite effect was observed in participants assigned to the
low-fat diet group (P = 0.02 and
0.04, respectively).

The fruitful data derived from gene-diet interaction analyses in the
randomized clinical trials may provide a promising prospective of personalized
direct response to dietary interventions. However, as mentioned above,
replication, functional exploration, and translation of the findings into
personalized diet interventions remain the chief challenges.

CONCLUSION

Though previous studies on gene-diet interaction have provided
preliminary but promising evidence, it is notable that most of them are
generally limited by lack of replication. Because of the observational nature
of these studies, confounding and reverse causation are inevitable. Improvement
in measuring dietary factors in population studies is another major issue.
Study shows that moderate decreases in the accuracy of measurement of dietary
factors may lead to a 20-fold reduction in statistical power to detect an
interaction [56]. Moreover, conventional statistical approaches are usually
underpowered to detect meaningful gene-diet interactions. Hence, a range of new
methods have been addressed these challenges, especially on a genome-wide scale
[57,58]. Breakthrough in the field will heavily rely on advances in methodology
development and collective efforts of well-designed, prospective cohorts with comprehensive
dietary information. Large-scale collaborations to detect gene-diet
interactions in the randomized controlled trials are urgently needed.

It remains debatable how to
translate statistically significant interactions into biological
interactions. Advance in high-throughput genotyping technology will facilitate
the service of direct-to-consumer genetic testing; and raise great hope that
genetic testing will pave the way to personalized prevention and medicine. It
could be imagined that the information from genetic and molecular biomarker
screening in patients will be taken into account in the prescription of
lifestyle such as dietary choice and drug therapy for diabetes prevention or
management. Public health practice will not be able to ignore the evidence from
studies of gene-diet interactions in the near future.

ACKNOWLEDGEMENTS

This work was supported by grants from the National Natural Science
Foundation of China [81471062 and 81270877], and the Shanghai Pujiang Project
(14PJD024).